In humans, it is well established that HIV-1 infection adversely affects the thymus in both children and adults [7, 12]. However, a recent study showed that long term survivors of paediatric HIV infection appear to have retained or recovered thymic volume and thymic activity approximating uninfected youths . Yet the consequences of this thymic inhibition are worse in children, which has been proposed as one cause of the rapid progression of the disease [14–16]. Early ART in HIV-infected children has proven to induce an early immune reconstitution that correlates with the increase in thymus volume . ART has also proven to be effective in recovering appropriate CD4+ levels in HIV-infected patients with low CD4+ counts [5, 18–21], possibly through the production of new T cells in the thymus. This is particularly relevant for children, who have a smaller T-cell pool and thus rely more heavily upon thymic output for the generation of immune-competent memory T cells.
In this study, we observed that HIV-infected patients have lower thymic production than healthy controls. This inhibitory effect on the thymus may be due to the ability of HIV to infect and destroy thymocytes . This would decrease the thymic production of new T cells and hinder both the appropriate maturation of the child's immune system and the reconstitution of cells lost due to the infection. When the thymic function of these HIV+ children on ART is analysed by the assessment of TRECs, it can be seen that the decrease in the viral load leads to a marked rise in thymic function [23, 24], and it correlates well with the recovery of CD4+ T-cell population [5, 6, 24–26].
In this study, we analyzed, as a whole, different aspects of immunity in HIV-1 infected patients on HAART with a previous moderate to severe immunosuppression state and who had been able to recover "normal" CD4+ T-cell counts (>500 cells/μl). Interestingly, HIV-Rec-adults had lower TREC Z-score levels than HIV-Rec-children. Therefore, our results contribute new findings and extend the previous data indicating that T-cell reconstitution in HIV-adults is mainly thymus-independent . However, HIV-Rec-adults had detectable TREC levels, although lower than healthy-adults, indicating their thymus was somewhat functional [11, 27]. In addition, HIV-adults had naïve CD4+ and CD8+ counts too high to be explained by the low TREC values observed in peripheral blood. The HIV-adults could still have a defective immune system despite normal recovery of CD4+ counts, although we cannot determine this since we do not have data on their TCR repertoire. Furthermore, HIV-children had a mainly thymus-dependent immune reconstitution [5, 28]. Thymic function of HIV-Rec-children had a greater capacity for recovery during severe HIV-infection, and they seemed to be less affected than the HIV-Rec-adults when TREC Z-score values were compared.
Interestingly, HIV-infected patients have abnormally high plasma levels of IL-7 associated with low counts of CD4+ . This suggests that low CD4+ counts should stimulate peripheral dendritic cells and lymphatic ganglia to produce IL-7, in an attempt to activate the mechanisms that allow cell repopulation . By contrast, other studies have suggested that plasma IL-7 levels may simply reflect the dynamics of binding secreted IL-7 to T cells: the fewer circulating T cells, the greater amount of free IL-7 . However, these high levels of IL-7 are ineffective in adults since no increase in thymic production or recuperation of the CD4+ T-cell repertoire has been observed, possibly due to the limited ability of the adult thymus to produce new T cells.
Thus, better thymic function in HIV-children may allow for the maintaining of a high output of naïve T cells resulting in lower IL-7 levels . In contrast, the thymus of HIV-adults generated less naïve T cells, making it necessary for more IL-7 to generate T cells by antigen-independent peripheral expansion [7, 27]. Therefore, the high values of IL-7 could be considered normal in HIV-adults and their immune reconstitution via stimulation T cell peripheral expansion may be more IL-7-dependent. However, a role of the thymus cannot be discarded in immune reconstitution in HIV-adults.
In our experience, high levels of IL-7 in children with lower CD4+ counts lead to a dramatic increase in the thymic production of new T cells and a marked recovery of CD4+ counts . This increase in thymic function takes place whenever viral load levels are low enough. Then, with the recovery of CD4+ counts, IL-7 returns to basal values as a consequence of a feedback mechanism .
Among HIV-children, we found that the thymic function of HIV-Rec-children appears to be normal, although it is well-known that HIV-infection could produce irreversible injury to the thymus of HIV-patients with AIDS . However, high IL-7 values in HIV-Rec-children could increase the thymic output, increasing TRECs values and compensating for the faulty thymic function. It is also possible that IL-7 stimulates the production of T cells by antigen-independent peripheral expansion . It is unclear why HIV-patients had a deficient de novo generation of CD4+ but not of CD8+. Extrathymic CD8+ but not CD4+ lymphopoiesis has been documented in mice, which if extrapolated to humans could partially explain those differences [32, 33]. Alternatively, this finding could be explained by elevated peripheral proliferation of naïve CD4+ and CD8+ .
A limitation of the study could be that immunological recovery was dependent on sustained VL suppression and efficacy of antiretrovirals that contribute to the HAART regimen. In this study, the size of groups was very small and we could not make strata according to antiretroviral therapy and sustained VL suppression periods to check the possible effect of these two factors. Another limitation of our study was that there was a difference between the age of healthy adults of the control group and HIV-Rec-adults. However, we think this difference has a low impact on the TREC levels in adults, since all of the subjects were adults inside an age range of approximately 25–40 years, Harris et al  in a previous study showed that thymic abundance was not inversely correlated with age in HIV-infected adults and the variation in the 25–40 year-old range is minimal.